Claudia Kronnerwetter

Human CLP1 Mutations Alter tRNA Biogenesis, Affecting Both Peripheral and Central Nervous System Function

CLP1 is a RNA kinase involved in tRNA splicing. Recently, CLP1 kinase-dead mice were shown to display a neuromuscular disorder with loss of motor neurons and muscle paralysis. Human genome analyses now identified a CLP1 homozygous missense mutation (p.R140H) in five unrelated families, leading to a loss of CLP1 interaction with the tRNA splicing endonuclease (TSEN) complex, largely reduced pre-tRNA cleavage activity, and accumulation of linear tRNA introns. The affected individuals develop severe motor-sensory defects, cortical dysgenesis, and microcephaly. Mice carrying kinase-dead CLP1 also displayed microcephaly and reduced cortical brain volume due to the enhanced cell death of neuronal progenitors that is associated with reduced numbers of cortical neurons. Our data elucidate a neurological syndrome defined by CLP1 mutations that impair tRNA splicing. Reduction of a founder mutation to homozygosity illustrates the importance of rare variations in disease and supports the clan genomics hypothesis.

Beyond Noise: Using Temporal ICA to Extract Meaningful Information from High-Frequency fMRI Signal Fluctuations during Rest

Analysis of resting-state networks using fMRI usually ignores high-frequency fluctuations in the BOLD signal – be it because of low TR prohibiting the analysis of fluctuations with frequencies higher than 0.25 Hz (for a typical TR of 2 s), or because of the application of a bandpass filter (commonly restricting the signal to frequencies lower than 0.1 Hz). While the standard model of convolving neuronal activity with a hemodynamic response function suggests that the signal of interest in fMRI is characterized by slow fluctuation, it is in fact unclear whether the high-frequency dynamics of the signal consists of noise only. In this study, 10 subjects were scanned at 3 T during 6 min of rest using a multiband EPI sequence with a TR of 354 ms to critically sample fluctuations of up to 1.4 Hz. Preprocessed data were high-pass filtered to include only frequencies above 0.25 Hz, and voxelwise whole-brain temporal ICA (tICA) was used to identify consistent high-frequency signals. The resulting components include physiological background signal sources, most notably pulsation and heart-beat components, that can be specifically identified and localized with the method presented here. Perhaps more surprisingly, common resting-state networks like the default-mode network also emerge as separate tICA components. This means that high-frequency oscillations sampled with a rather T1-weighted contrast still contain specific information on these resting-state networks to consistently identify them, not consistent with the commonly held view that these networks operate on low-frequency fluctuations alone. Consequently, the use of bandpass filters in resting-state data analysis should be reconsidered, since this step eliminates potentially relevant information. Instead, more specific methods for the elimination of physiological background signals, for example by regression of physiological noise components, might prove to be viable alternatives.

The spectral diversity of resting-state fluctuations in the human brain.

In order to assess whole-brain resting-state fluctuations at a wide range of frequencies, resting-state fMRI data of 20 healthy subjects were acquired using a multiband EPI sequence with a low TR (354 ms) and compared to 20 resting-state datasets from standard, high-TR (1800 ms) EPI scans. The spatial distribution of fluctuations in various frequency ranges are analyzed along with the spectra of the time-series in voxels from different regions of interest. Functional connectivity specific to different frequency ranges (<0.1 Hz; 0.1–0.25 Hz; 0.25–0.75 Hz; 0.75–1.4 Hz) was computed for both the low-TR and (for the two lower-frequency ranges) the high-TR datasets using bandpass filters. In the low-TR data, cortical regions exhibited highest contribution of low-frequency fluctuations and the most marked low-frequency peak in the spectrum, while the time courses in subcortical grey matter regions as well as the insula were strongly contaminated by high-frequency signals. White matter and CSF regions had highest contribution of high-frequency fluctuations and a mostly flat power spectrum. In the high-TR data, the basic patterns of the low-TR data can be recognized, but the high-frequency proportions of the signal fluctuations are folded into the low frequency range, thus obfuscating the low-frequency dynamics. Regions with higher proportion of high-frequency oscillations in the low-TR data showed flatter power spectra in the high-TR data due to aliasing of the high-frequency signal components, leading to loss of specificity in the signal from these regions in high-TR data. Functional connectivity analyses showed that there are correlations between resting-state signal fluctuations of distant brain regions even at high frequencies, which can be measured using low-TR fMRI. On the other hand, in the high-TR data, loss of specificity of measured fluctuations leads to lower sensitivity in detecting functional connectivity. This underlines the advantages of low-TR EPI sequences for resting-state and potentially also task-related fMRI experiments.

Longitudinal brain imaging of five malignant glioma patients treated with bevacizumab using susceptibility-weighted magnetic resonance imaging at 7 T

Malignant glioma is a rare tumor type characterized by prominent vascular proliferation. Antiangiogenic therapy with the monoclonal antibody bevacizumab is considered as a promising therapeutic strategy, although the effect on tumor vascularization is unclear. High-field susceptibility-weighted imaging (SWI) visualizes the microvasculature and may contribute to the investigation of antiangiogenic therapy responses in gliomas. We prospectively studied five adult malignant glioma patients treated with bevacizumab-containing regimens. In each patient, we performed three 7-T SWI and T1-weighted imaging investigations (baseline and 2 and 4 weeks after the start of bevacizumab treatment). In addition, we imaged a postmortem brain of a patient with glioblastoma using 7-T SWI and performed detailed histopathological analysis. We observed almost total resolution of brain edema in three of five patients after initiation of bevacizumab therapy. In one case with rapid increase of the lesion size despite bevacizumab therapy, SWI showed progressive increase of irregular hypointense structures, most likely corresponding to increasing amounts of pathological microvasculature. In one case with progressive neurological decline, 7-T images showed multiple intratumoral microhemorrhages after the first bevacizumab application. Correlation of postmortem neuroimaging with histopathology confirmed that SWI-positive structures correspond to tumor vasculature. The experience from our case series indicates that longitudinal 7-T SWI seems to be an appropriate method for investigation of changes in brain tumor vascularization over time under antiangiogenic therapy.

Comparison of 3 T and 7 T MRI clinical sequences for ankle imaging

The purpose of this study was to compare 3T and 7T signal-to-noise and contrast-to noise ratios of clinical sequences for imaging of the ankles with optimized sequences and dedicated coils. Ten healthy volunteers were examined consecutively on both systems with three clinical sequences: (1) 3D gradient-echo, T(1)-weighted; (2) 2D fast spin-echo, PD-weighted; and (3) 2D spin-echo, T(1)-weighted. SNR was calculated for six regions: cartilage; bone; muscle; synovial fluid; Achilles tendon; and Kagers fat-pad. CNR was obtained for cartilage/bone, cartilage/fluid, cartilage/muscle, and muscle/fat-pad, and compared by a one-way ANOVA test for repeated measures. Mean SNR significantly increased at 7T compared to 3T for 3D GRE, and 2D TSE was 60.9% and 86.7%, respectively. In contrast, an average SNR decrease of almost 25% was observed in the 2D SE sequence. A CNR increase was observed in 2D TSE images, and in most 3D GRE images. There was a substantial benefit from ultra high-field MR imaging of ankles with routine clinical sequences at 7T compared to 3T. Higher SNR and CNR at ultra-high field MR scanners may be useful in clinical practice for ankle imaging. However, carefully optimized protocols and dedicated extremity coils are necessary to obtain optimal results.

The veins of the nucleus dentatus: anatomical and radiological findings.

The veins of the dentate nucleus are composed of several channels draining the external surface and one single vein draining the internal surface. We analyzed specimens of the human cerebellum and described the central vein of the nucleus dentatus as the main venous outflow of the nucleus. The central vein of the nucleus dentatus is formed by a network of smaller vessels draining the sinuosities of the gray matter; it emerges from the hilum of the nucleus and runs along the superior cerebellar peduncle, opening in the anterior vermian vein. We looked for this structure and for the surrounding veins on ultra-high-field (7 Tesla) MR, using susceptibility-weighted imaging. An anatomical and radiological description of the veins of the dentate nucleus is provided, with some remarks on the future clinical applications that these findings could provide.

Susceptibility-weighted imaging at 7 T: Improved diagnosis of cerebral cavernous malformations and associated developmental venous anomalies

Background and aim In the diagnosis of cerebral cavernous malformations (CCMs) magnetic resonance imaging is established as the gold standard. Conventional MRI techniques have their drawbacks in the diagnosis of CCMs and associated venous malformations (DVAs). The aim of our study was to evaluate susceptibility weighted imaging SWI for the detection of CCM and associated DVAs at 7 T in comparison with 3 T. Patients and methods 24 patients (14 female, 10 male; median age: 38.3 y (21.1 y–69.1 y) were included in the study. Patients enrolled in the study received a 3 T and a 7 T MRI on the same day. The following sequences were applied on both field strengths: a T1 weighted 3D GRE sequence (MP-RAGE) and a SWI sequence. After obtaining the study MRIs, eleven patients underwent surgery and 13 patients were followed conservatively or were treated radio-surgically. Results Patients initially presented with haemorrhage (n = 4, 16.7%), seizures (n = 2, 8.3%) or other neurology (n = 18, 75.0%). For surgical resected lesions histopathological findings verified the diagnosis of CCMs. A significantly higher number of CCMs was diagnosed at 7 T SWI sequences compared with 3 T SWI (p < 0.05). Additionally diagnosed lesions on 7 T MRI were significantly smaller compared to the initial lesions on 3 T MRIs (p < 0.001). Further, more associated DVAs were diagnosed at 7 T MRI compared to 3 T MRI. Conclusion SWI sequences at ultra-high-field MRI improve the diagnosis of CCMs and associated DVAs and therefore add important pre-operative information.

Anatomy and variants of the triangular fibrocartilage complex and its MR appearance at 3 and 7T.

Due to the small size and complexity of its constituents, the triangular fibrocartilage complex (TFCC) has been a challenging structure for magnetic resonance (MR) imaging. Higher-field MR units, at 3T and 7T, with increased spatial resolution and the development of novel MR sequences, are promising tools for an improved visualization of the ulnocarpal complex. Anatomically, the TFCC consists of the TFC proper, the ulnomeniscal homolog, the ulnar collateral ligament, the ulnotriquetral and ulnolunate ligament, and radioulnar ligaments at the volar (palmar) and the dorsal side, as well as the sheath of the extensor carpi ulnaris tendon and the capsule of the distal radioulnar joint. This article describes the normal anatomy of the TFCC and its appearance on high-field MRI. Anatomical variants, such as the positive ulnar variance, and changes during pronation and supination are addressed.

7-Tesla MRI demonstrates absence of structural lesions in patients with vestibular paroxysmia

Vestibular parxoysmia (VP) is a rare vestibular disorder. A neurovascular cross-compression (NVCC) between the vestibulochochlear nerve and an artery seems to be responsible for short attacks of vertigo in this entity. An NVCC can be seen in up to every fourth subject. The significance of these findings is not clear, as not all subjects suffer from symptoms. The aim of the present study was to assess possible structural lesions of the vestibulocochlear nerve by means of high field magnetic resonance imaging (MRI), and whether high field MRI may help to differentiate symptomatic from asymptomatic subjects. 7 Tesla MRI was performed in six patients with VP and confirmed NVCC seen on 1.5 and 3.0 MRI. No structural abnormalities were detected in any of the patients in 7 Tesla MRI. These findings imply that high field MRI does not help to differentiate between symptomatic and asymptomatic NVCC and that the symptoms of VP are not caused by structural nerve lesions. This supports the hypothesis that the nystagmus associated with VP has to be conceived pathophysiologically as an excitatory vestibular phenomenon, being not related to vestibular hypofunction. 7 Tesla MRI outperforms conventional MRI in image resolution and may be useful in vestibular disorders.

High-Resolution Axonal Bundle (Fascicle) Assessment and Triple-Echo Steady-State T2 Mapping of the Median Nerve at 7 T: Preliminary Experience.

ObjectivesThe aims of this preliminary study were to determine the number of axonal bundles (fascicles) in the median nerve,1 using a high-resolution, proton density (PD)–turbo spin echo (TSE) fat suppression sequence, and to determine normative T2 values, measured by triple-echo steady state, of the median nerve in healthy volunteers and in patients with idiopathic carpal tunnel syndrome (CTS), at 7 T.2 Materials and MethodsThis prospective study was approved by the local ethics committee and conducted between March 2014 and January 2015. All study participants gave written informed consent. Six healthy volunteers (30 ± 12 years) and 5 patients with CTS (44 ± 16 years) were included. Measurements were performed on both wrists in all volunteers and on the affected wrist in patients (3 right, 2 left). Based on 5-point scales, 2 readers assessed image quality (1, very poor; 5, very good) and the presence of artifacts that might have a possible influence on fascicle determination (1, severe artifacts; 5, no artifacts) and counted the number of fascicles independently on the PD-TSE sequences. Furthermore, T2 values by region of interest analysis were assessed. Student t tests, a hierarchic linear model, and intraclass correlation coefficients (ICCs) were used for statistical analysis. ResultsProton density-TSE image quality and artifacts revealed a median of 5 in healthy volunteers and 4 in patients with CTS for both readers. Fascicle count of the median nerve ranged from 13 to 23 in all subjects, with an ICC of 0.87 (95% confidence interval [CI], 0.67–0.95). T2 values were significantly higher (P = 0.023) in patients (24.27 ± 0.97 milliseconds [95% CI, 22.19–26.38]) compared with healthy volunteers (21.01 ± 0.65 milliseconds [95% CI, 19.61–22.41]). The ICC for all T2 values was 0.97 (95% CI, 0.96–0.98). ConclusionsThis study shows the possibility of fascicle determination of the median nerve in healthy volunteers and patients with CTS (although probably less accurately) with high-resolution 7 T magnetic resonance imaging, as well as significantly higher T2 values in patients with CTS, which seems to be associated with pathophysiological nerve changes.